1. Field of the Invention
The invention disclosed herein is directed to inducing an MHC class-I restricted immune response and controlling the nature and magnitude of the response, thereby promoting effective immunologic intervention in pathogenic processes. The invention relates to immunogenic compositions that can stimulate a cellular immune response against a target cell. Disclosed herein is an immunogenic composition comprising a nucleic acid construct encoding the CTL epitopes PRAME425-433 and PSMA288-297 or a cross-reactive analogue of either or both of epitopes. The invention also provides methods of using the described immunogenic composition to elicit a balanced immune response in a subject to whom such compositions are administered.
2. Description of the Related Art
Cancer generally develops when cells in a part of the body continue to grow and divide in an unorderly manner unlike normal cells that grow, divide, and die in an orderly fashion. Although there are many kinds of cancer, they usually start because of out-of-control growth of abnormal cells.
Usual treatment options for cancer include surgery, radiation therapy, and chemotherapy. A fourth branch of treatment is developing, which is referred to as immunotherapy. Immunotherapies attempt to help the immune system recognize cancer cells, and/or to strengthen a response against cancer cells in order to destroy the cancer. Immunotherapies include active and passive immunotherapies. Active immunotherapies attempt to stimulate the body's own immune system to fight the disease. Passive immunotherapies generally do not rely on the body to attack the disease; instead, they use immune system components (such as antibodies) created outside of the patient's body.
Despite various types of cancer treatments, a continuing need exists for additional treatment options. Manipulation of the immune system by use of an anticancer vaccine is one such approach.
To generate a vaccine or other immunogenic composition, an antigen or epitope against which an immune response can be mounted is introduced to a subject. Although neoplastic (cancer) cells are derived from and therefore are substantially identical to normal cells on a genetic level, many neoplastic cells are known to present tumor-associated antigens (TuAAs). In theory, these antigens could be used by a subject's immune system to recognize and attack the neoplastic cells as foreign. Unfortunately, neoplastic cells generally appear to be ignored by the host's immune system.
The immune system can be categorized into two discrete effector arms. The first is innate immunity, which involves numerous cellular components and soluble factors that respond to all infectious challenges. The other is the adaptive immune response, which is customized to respond specifically to precise epitopes from infectious agents. The adaptive immune response is further broken down into two effector arms known as the humoral and cellular immune systems. The humoral arm is centered on the production of antibodies by B-lymphocytes while the cellular arm involves the killer cell activity of cytotoxic T lymphocytes.
Cytotoxic T lymphocytes (CTL) do not recognize epitopes on the infectious agents themselves. Rather, CTL detect fragments of antigens derived from infectious agents that are displayed on the surface of infected cells. As a result antigens are visible to CTL only after they have been processed by the infected cell and thus displayed on the surface of the cell.
The antigen processing and display system on the surface of cells has been well established. CTL recognize short peptide antigens, which are displayed on the surface in non-covalent association with class I major histocompatibility complex molecules (MHC). These class I peptides are in turn derived from the degradation of cytosolic proteins.
In most instances, neoplastic processes evolve to avoid the immune defense mechanisms by employing a range of strategies that result in immune ignorance, tolerance or deviation. Methods that effectively break immune tolerance or repair immune deviation against antigens expressed on cancer cells have been described in the literature (Okano F, et al. J Immunol. 2005, March 1; 174(5):2645-52; Mocellin S, et al., Exp Cell Res. 2004 Oct. 1; 299(2):267-78; Banat G A, et al., Cancer Immunol Immunother. 2001 January; 49(11):573-86) and despite their association with significant levels of systemic immunity, rarely result in reduction of tumor burden. Significant limiting factors impacting this process are sub-optimal trafficking, local activation and/or activity of anti-tumoral effector cells. In fact, it has been shown in most instances that the intra-tumoral presence of immune cells is a rare occurrence—compared to that associated with inflammatory processes such as organ rejection, infections or autoimmune syndromes.
The immune response resulting from exposure to antigens (in a natural context or upon vaccination) that encompass multiple epitopes is inherently associated with a hierarchy relative to the magnitude of the immune response against different, individual epitopes. This occurs in the case of T cell epitopes such as MHC class I and class II restricted epitopes, where dominance and subdominance has been well documented. Dominant epitopes are those that elicit prominent and specific expansions of T cells; whereas subdominant epitopes elicit relatively reduced responses characterized by a limited expansion of specific T cells with diminished functionality.
There are multiple reasons for an immune response to focus on a subset of epitopes within an antigen, regardless of whether the antigen is natural or engineered. These reasons include but are not limited to the following: efficacy of generation of certain peptides or polypeptide precursors within proteasomes (for class I restricted) or endosomes (for class II restricted); their selective transport via TAP (for class I peptides) and alternative mechanisms to compartments where loading onto MHC occurs; their affinity for MHC molecules relative to chaperones or the invariant polypeptide chain that occupies the peptide-binding cleft of nascent MHC molecules and relative to other competing peptides resulting from processing of the same or alternative substrates; the stability of the resulting MHC-peptide complex; and the functionality of T cell repertoire.
In addition, two or more epitopes from different antigens brought together on the same artificial molecule assume a dominant/subdominant relationship due to their intrinsic properties (such as those described above). This limits the practical applicability of composite molecules for the purpose of immunotherapy, particularly when co-targeting of cancer cells (neoplastic) and stromal elements (such as neovasculature) is pursued.